Serotonin (5-HT) neurotransmission plays an important role in numerous physiological processes both in health and in psychiatric disorders. For example, 5-HT has been implicated in the regulation of feeding behavior. 5-HT is believed to work by inducing a feeling of fullness or satiety so eating stops earlier and fewer calories are consumed. It has been shown that a stimulatory action of 5-HT on the 5-HT2C receptor plays an important role in the control of eating and in the anti-obesity effect of d-fenfluramine. As the 5-HT2C receptor is expressed in high density in the brain (notably in the limbic structures, extrapyramidal pathways, thalamus and hypothalamus i.e. PVN and DMH, and predominantly in the choroid plexus) and is expressed in low density or is absent in peripheral tissues, a selective 5-HT2C receptor agonist can be a more effective and safe anti-obesity agent. Also, 5-HT2C knockout mice are overweight with cognitive impairment and susceptibility to seizure. Thus, the 5-HT2C receptor is recognized as a well-accepted receptor target for the treatment of obesity, psychiatric, and other disorders.
Lorcaserin hydrochloride (8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride) is an agonist of the 5-HT2C receptor and shows effectiveness at reducing obesity in animal models and humans. Patients enrolled in a 12-week Phase IIb clinical trial achieved a highly statistically significant mean weight loss of 4.0, 5.7, and 7.9 pounds at daily doses of 10 mg, 15 mg, and 20 mg (10 mg dosed twice daily), respectively, compared to 0.7 pounds for the placebo group. The proportion of patients completing the treatment period who achieved a 5% or greater weight loss from baseline were 13%, 20%, and 31% at daily doses of 10 mg, 15 mg, and 20 mg, respectively, compared with 2% in the placebo group. This data, showing statistically significant, progressive, and dose-dependant weight loss, coupled with the drug's favorable tolerability profile make locaserin hydrochloride an attractive new therapy for obesity, and accordingly, Phase III clinical trials are underway. Various synthetic routes to locaserin hydrochloride, its related salts, enantiomers, crystalline forms, and intermediates, have been reported in WO 2005/019179, WO 2006/069363, and U.S. Pat. No. 6,953,787.
In view of the growing demand for compounds for the treatment of disorders related to the 5-HT2C receptor, new and more efficient routes to 3-benzazepines, including locaserin hydrochloride, are needed. The processes and compounds described herein help meet these and other needs.